Introduction: Clinical Presentation of Gastroesophageal Cancer

DR LOVE: Good afternoon, everyone. I'm Neil Love from Research To Practice and welcome back to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is the tenth of 11 programs we're doing here at the ONS Congress. We've been coming here for 17 years and it's been such a great week. This afternoon we're going to talk about gastroesophageal cancers. We have a great faculty here today. We have another faculty member who got kind of stuck in an airport, but Manish Shah from the Weill Cornell Medical Center in New York. Happy to see you here, Manish. I'm glad you could participate virtually. From our nursing faculty, we have Ms Brooke Parker from the UCHealth Cancer Care in Aurora, Colorado, right near here, Ms Michal Segal from Memorial Sloan Kettering Cancer Center in New York City and Dr Sunnie Kim from the University of Colorado Cancer Center in Aurora. Thanks for the good weather here, Sunnie. It was like 38 degrees a couple of days before we started. I came here from Miami and forgot my coat. So fortunately I haven't needed it.

So we will, as in all of these programs, be talking about the use of unapproved agents and regimens as part of our discussion. Please consult the official prescribing information for all the products that we discuss today for more information.

We are recording all 11 of these programs. And we'll let you know when it's available in the next week or 2 to be viewed by your colleagues who are not able to make it, including on our podcast series Oncology Nursing Update that we started recently. You take your phone, go to podcasts, hit search, put in Oncology Nursing Update. We already have a couple of programs on there and we're going to be loading in all 11 of these over the next couple of weeks and more to come.

As I mentioned, this is a whole series of programs. We do this every year. It really runs parallel to the ONS Congress. We really try to get into the strategy that medical oncologists use in making decisions, how they look at clinical research and decide how to incorporate particularly new therapies into practice. And there are a lot of new therapies in oncology and a lot in gastrointestinal cancers.

More than anything, this is really an opportunity to pick the brains of our faculty. We always love rounds. I loved rounds as an intern and felt like that was the best way to learn. So we really incorporated a round-like approach to what we do in education. It's such a thrill to be working with such a great faculty.

So let's start out. We're going to talk about gastroesophageal cancers. We're going to start out with a little bit of an overview. We typically think about esophageal cancer and gastric cancer, but they really come together in many ways. First, we'll talk about the management of localized gastroesophageal cancers, particularly locally advanced, which is the way localized disease usually presents. Then we'll talk about metastatic disease and particularly the revolution in immunotherapy and the use of checkpoint inhibitors. We now have 3 very similar agents available in the metastatic setting. Then we'll get into one of the most exciting areas and challenging areas in oncology, a new agent, zolbetuximab, used in patients with claudin 18.2 target in their tumor. We've talked all week long about targeted therapy, looking inside the tumor for genomic alterations. This is another example. Another effective drug but also with a very challenging side-effect profile that we're going to talk about. And finally we'll finish out talking about a subject that's come up a number of times this week, HER2-positive disease. We used to think about that mainly for breast cancer and we talked about that Wednesday night. But now we're talking about many different cancers being treated with anti-HER therapy, particularly the antibody-drug conjugate trastuzumab/deruxtecan. And we'll get into that in a second.

But just to kind of sort of dive into this a little bit in terms of what esophageal cancer or esophago-gastric cancer is. Manish, maybe you can talk a little bit about how you think about it in terms of where these cancers occur and how it affects the way you think through the case.

DR SHAH: So esophago-gastric cancer, so this is a pictorial of the esophagus and stomach. And although it's essentially one long tube, on the right you see the different molecular phenotypes of esophageal squamous cell cancer, that's in the maroon, and then you have GE junction tumors, which is purple, EBV, MSI-high, which is light blue, and then diffuse or genomically stable, which is green. And what you see is that as you go from the throat down to the GE junction, you have kind of a change in both histology, it goes from squamous cell cancer to adenocarcinoma, but that's also associated with changes in the molecular phenotype. And for localized disease, that may play a role as we'll discuss with the case and with the discussion. But for gastric cancer, and I know we're talking about esophageal primarily, but for gastric cancer, there is more heterogeneity and that's going to play a role for localized disease for that cancer as well.

DR LOVE: Sunnie, can you talk a little bit about what's been going on in terms of the incidence of these tumors? And also a little bit about MSI high versus MSI stable? We did a program this morning on endometrial cancer where we began to get into that. So what's going on right now in terms of the incidence of these cancers? What do you see in terms of geographic differences? And can you explain a little bit about what MSI high is?

DR KIM: Yeah. At least in the United States, the incidence of squamous cell cancer has gone down. The classic risk factors for squamous cell esophageal cancer is smoking and drinking. So that's improved. With our GEJ adenocarcinoma, we've seen a bit of an increase in the incidence of that. Those risk factors are the classic western risk factors, GERD, obesity. So those are the overall trends. In terms of MSI high, so this will also be in my presentation, but there are 4 very important proteins called mismatch repair proteins. And if any of those are absent, it actually prevents proper DNA base pair repair causing these mutations in the tumor that can be more treated with immunotherapy. In the localized setting, we actually see MSI high as high as 15% of cases. In the metastatic setting, it can be about 5%. But it's very important to identify those patients both in the localized and metastatic setting because there are significant treatment implications.

DR LOVE: And the big implication is there are a lot of mutations in these tumors. If you look at it there's an assay called tumor mutation burden. It's very high. In these patients, the tumors are very sensitive to checkpoint inhibitors and we'll get into that in a second. Manish, also we see 2 different histologies. You briefly mentioned that. Can you talk a little bit more about sort of the difference between adenocarcinoma and squamous cell and where you see these?

DR SHAH: Yeah, absolutely. So squamous cell cancer comes from the barrier cells, the squamous epithelium, which is on your skin. It's actually in your mouth and then it goes into the upper part of the esophagus. Adenocarcinoma comes from cells that are intestinalized. These are cells that have more of a glandular function. They're not intended to form barriers, they're intended to handle secretions and to try to collect material. So intestinal histology typically it should be in the stomach in the small intestine and the colon, but everyone in the room knows about Barrett's esophagus. So patients who have risk factors like obesity or a lot of reflux, they can reflux acid from their stomach into the esophagus and that leads to an intestinalization of the esophagus. And that leads to the intestinal type mucosa, Barrett's esophagus, and then eventually there's a risk of adenocarcinoma in the esophagus as well. Historically, we've treated both histologies very similarly with chemotherapy and radiation for localized disease with surgery. But we're learning that really not only are they very clearly different, but they behave differently to the different treatments and that plays a role in terms of what we recommend for localized disease. So on this slide here, the figure on the left is the adenocarcinoma and what you're supposed to kind of identify are these finger-like glands. They're circular glands that are in the mucosa. On the right, is a squamous cell cancer. You don't really see those glands and you think of this as like a barrier type of a cancer. And so they have different mutations and different sensitivities. So that's a key thing to understand. So when you have a new diagnosis of esophageal cancer, you want to know what the histology is.

DR LOVE: So in a second we'll hear about a case that Manish has of a 67-year-old man, but I'm just kind of curious, Brooke, of course, a patient might present with symptoms of metastatic disease, that's not uncommon. But what kind of local symptoms do you see patients have with these cancers? In medical school, you learn esophageal cancer typically they have trouble swallowing first with solids and then liquids. Manish's patient had pain after eating. Can you talk a little bit about some of the local symptoms you see in these patients?

MS PARKER: Yes, absolutely. Well, you kind of hit the nail on the head where typically patients experience some degree of dysphagia. So patients will have trouble swallowing and it can get as severe where they can even have difficulties drinking water and things like that. Sometimes they'll experience more like heartburn and just like more of a generalized pain as well.

DR LOVE: Anything, Michal, you want to add to that? And also one of the things we get into here as a theme in our work as we talk about cases and particularly individualizing to the patient. It's not only the tumor characteristics and the symptoms from the tumor, but the patient themselves. And one of the themes we have over the years has been, why was it different to take care of this patient than another patient in a same oncology situation but a different person? What are some of the things you're thinking about when you see a patient with this for the first time that you want to assess beyond the tumor? And anything you want to add to what Brooke was saying about the types of symptoms they have?

MS SEGAL: Yeah, so like Brooke said, patients come in with unintended weight loss, difficulty swallowing or dysphagia, painful swallowing, abdominal pain. And some patients can actually feel adenopathy. Some people come in in the context of GERD having unresolving cough or hoarseness. When patients come in, you want to assess for those symptoms but also their support system at home. See what kind of help they have and what kind of help they need. Take an assessment of if they have kids and if they have travel needs so we can get social work involved and there's other resources that we can connect them to.

DR LOVE: So let's get into this case. Manish, this is a 67-year-old attorney. Before you get into the sort of medical part or oncologic part of his care, can you talk a little bit about him as a person?

DR SHAH: Yeah, for sure. So he is, like many attorneys, he's a bit of a workaholic, a 100-hour week is not unusual. And so for him it was unusual that he felt that he needed to take a rest during the middle of the day a few days a week. So that was the first clue. I didn't mention. He did have a 15-pound weight loss. And in this current era of the GLP-4 inhibitors, he was thinking that that was a good thing. I think that it's one thing that we have to remember. Someone might have symptoms of pain and anemia. Weight loss you have to think, even if it's intentional, it may actually also be associated with some pathology here. But the main thing that happened to him is that he felt more fatigue than usual and it was interfering with his work and so he thought he needed to get evaluated. Really nice guy. Father of 3. Just devastated by the diagnosis unfortunately.

DR LOVE: So I see here he had a biopsy. It looks like adenocarcinoma. You were just describing the way it looks. You can see the glands there. What about the workup? Did he have any evidence of metastatic disease?

DR SHAH: Right. So as is always the case in oncology, tissue is the issue. So you have to do the endoscopy. And we found that ulcer, on the previous slide here, that's that crater on the endoscopy there. And then the biopsy did show an adenocarcinoma that was an intestinal type and moderately differentiated. So the next step typically is a CAT scan and often a PET scan as well. A CAT scan is a good initial look to see if there's metastatic disease. But if the CAT scan is negative, a PET scan is actually, in fact, recommended because in about 15 to 20% of patients you'll identify occult metastatic disease, disease in metastatic lymph nodes or in the bone. He didn't seem to have that. Often we also do an endoscopic ultrasound. That's the figure on the left with the circle. That allows us to get a sense of how deep the tumor invades and then whether or not any lymph nodes are involved. So in terms of a staging strategy, you want to make sure that the patient doesn't have metastatic disease. And then if it's localized, you want to know, is it locally advanced? In which case you would need to do more than just surgery. Because there's lots of data that suggests that additional treatment, whether it's chemotherapy or chemoradiotherapy, is appropriate. Or is it an early-stage localized cancer where you might consider just surgery alone or just chemotherapy with radiation?

DR LOVE: Of course, we can see here he actually had a positive node. The FNA, fine needle aspiration, showed it was positive. And like many of these cases, he got perioperative or preoperative chemotherapy. We'll talk in a second about what would've happened if instead of adenocarcinoma in the stomach, he had esophageal cancer. But he got a very common approach to this before surgery, FLOT chemotherapy. Can you explain what it is? How patients generally tolerate it? And how did he do?

DR SHAH: Yeah, for sure. So FLOT is an acronym for a 3-drug chemotherapy regimen. There's actually 4 drugs. It's a misnomer. The L is leucovorin, which is a vitamin. So there's 3 chemotherapy drugs and a vitamin. F is fluorouracil, L, as I said, is leucovorin, O is oxaliplatin and T is Taxotere. The fluorouracil is given as a 24-hour infusion, different than FOLFOX, which is 48 hours. And then the other 3 drugs are given on day 1 of the infusion. This 3-drug regimen is an aggressive regimen. People do have side effects including hair loss and fatigue, myelosuppression, mucositis, things like that. And often people need to be supported with growth factors. The important thing here though is that this 3-drug regimen, FLOT, was superior to the previous MAGIC regimen that we used in the perioperative setting. And because of that, this is now the current standard for esophageal adenocarcinoma that's locally advanced. So you get 4 cycles of this. The treatment is every other week. So it's about 2 months of therapy. And then about a month later, the patient goes for resection.

And there are several things on this path report that are important to highlight. The first thing is first that there was residual cancer and that designation ypT3N0. The y means that there was previous treatment. P is pathologic. The T is the depth of invasion. So it went into the muscle layer, the third layer. And then no lymph nodes were involved. So there was still residual cancer. That's important. The other thing that's important though is in that first line it says, rare cancer cells. And this TRG score, it goes 0, 1, 2, 3, 4. 0 is a complete response, 1 is minimal residual cancer cells, which is what's described there. And patients who have a TRG 0 or 1, they have the best outcomes and best survival. So this is someone who had a major response to treatment even though there was still a Stage II cancer based on the pathology. So it's what we're seeing now often with FLOT. The complete response rate with FLOT is around 10 to 15%. The major path response rate, which is what he had, is around 30 to 40%. So it's really quite significant.

DR LOVE: How did he tolerate the FLOT? And what's his current situation?

DR SHAH: Yeah, great. So he did need a dose reduction. I counsel my patients that about half of them, maybe even 60 to 70%, will need some modification. He did develop neutropenia and fever after cycle 2. He had hair loss. He did develop some numbness and tingling because he's getting both the oxaliplatin and the docetaxel. But, I mean, all that being said, he was able to get through it. I think the advantage of doing FLOT in this setting is that you start and you already see the light at the end of the tunnel. You have to only get through 4 treatments. So he could tolerate, I mean, people can tolerate it because they say they're almost done. And the other thing is that, you know, I feel like these patients do need a lot of support. They benefit from phone calls. He did need hydration periodically throughout this. You just have to hold their hand a little bit to get through it. And if you're able to, you can get rewarded. I mean, there is an improvement in survival through this ordeal.

DR LOVE: Michal, what do you typically see with FLOT? I mean, it kind of has a reputation of being one of the tougher chemo regimens in oncology.

MS SEGAL: Definitely and we prepare our patients with that. We tell them that, listen, this is a heavy duty, it's a triple drug combo. For fatigue, take it easy. Don’t overdo yourself. Don't overextend your plans. What's nice, like Dr Shah said, is that it's a finite amount of time before they're set for surgery so they just need to get through it. Try to maintain their weight. Try to avoid weight loss. Take PRNs. Take your antiemetics at home. And don't be, some patients really want to be stoic. They don't want to complain but check-in with your patients, call them if they don't call you and really encourage them to call in and tell you if they're not managing at home. Once a week if they come in even for IV hydration, that can make a difference and be helpful.

DR LOVE: So in a second we're going to have Manish go through some of the clinical research data that led to these therapies but just sort of a little bit of a preview, Sunnie. Can you talk about how you would've approached the same situation again locally advanced but now, for example, a squamous cancer in the esophagus.

DR KIM: Yeah, squamous cell esophageal cancer is very much a different biology of tumor than adenocarcinoma. It's very radiosensitive. So the study that looked at perioperative chemo is not really applicable for squamous esophageal cancer. For those patients, I do offer preoperative concurrent chemoradiation. And as high as 50% of patients will experience a complete response actually from chemoradiation.

DR LOVE: What about post-op?

DR KIM: Post-op. So when these patients, after they go through surgery, if there's residual disease in the resected specimen, there is a study, which I think Manish will go through, called CheckMate 577. That showed that the addition of 1 year of nivolumab compared to placebo did improve what we call event-free survival, the time for the cancer to come back. So that is my current practice right now.

Management of Localized or Locally Advanced Gastroesophageal Cancers; Current and Future Role of Immune Checkpoint Inhibitors

DR LOVE: And checkpoint inhibitors is a major topic here today. We talked again a lot about it this morning but we're going to talk a lot about it today. We could talk about it all day long. There's so much to talk about. Manish, let's take a look at some of the clinical research data that led to these approaches.

DR SHAH: Absolutely. And thanks, Sunnie, for giving a preview. You could give these slides in your sleep as well. So locally advanced disease. So we talked a little bit about the epidemiology of esophageal cancer. It is the seventh leading cause of cancer deaths worldwide. It's not so prevalent in the United States, but there is an area in Southeast Asia, so that includes China and Japan, and then you also have the Middle East, India and Eastern Europe, you know, Ukraine and Poland. That's where there's a lot of esophageal cancer. But the key thing, and we talked about histology, in those areas the more prevent subtype is this squamous cell subtype. It has to do with perhaps diet and environment. Like in India, for example, they chew these betel leaves and that's associated with topical irritation. But the incidence does rise with age and it peaks in your 60s and 70s. There is a male predominance. In the United States, and we're actually the only country that can do this, we see that there is a disparity. It is actually much more prevalent in African American males as well as in Hispanics as well. So that's a little bit of the epidemiology.

So the CROSS regimen, so that was a randomized study of chemotherapy with radiation followed by surgery compared to surgery alone. And the real advantage of the CROSS regimen was that it was tolerable. Over 90% of patients were able to complete the chemotherapy and the radiation. About 20% had Grade 3 toxicity, which is not a high rate actually. It did improve the complete resection rate and the surgical morbidity and mortality was very, very similar between the regimens. So for many years, that regimen was considered the standard regimen. And these are the survival curves for patients who received chemotherapy with radiation followed by surgery, that's the green curve, versus the blue curve, which is surgery alone. And if you had squamous cell cancer, this is a combination of both squamous and adeno. If you put it up with squamous cell cancer, the curves are wider and more spread apart. So there's a bigger benefit for squamous cell cancer than there is for adenocarcinoma. But look at the survival difference, 50 months versus 26 months. Almost double. So really this is a real advance and this was relatively recent actually. Van Hagen published it in The New England Journal of Medicine within the last 8 years or so.

Building on the CROSS regimen, the CheckMate 577 looked at patients who received chemoradiotherapy and then they had surgery and then it was examining whether or not the addition of immunotherapy would have any benefit. So it was a 2:1 randomization. So about 800 patients were randomized. 530 got nivolumab and 260 got placebo. And the main outcome here is what Sunnie mentioned, event-free survival. So not having any event of a recurrence or death. And so again the green curve is nivolumab and you can see there is a significant improvement in event-free survival with the addition of nivolumab versus the placebo. Again if you look at the medians, 11 months versus 22 months, a doubling. So that's another big advance. So for many years, the standard was chemotherapy with radiation, the CROSS regimen specifically, followed by surgery and then if you had any residual disease, you would get adjuvant nivolumab. And this was for both squamous and adenocarcinoma. But remember for squamous cell cancer, the chemotherapy radiation probably works better.

The FLOT regimen is what we were talking about and this is what my patient got. And so, again, FLOT is shown here. Docetaxel, oxaliplatin, leucovorin, which is a vitamin, and fluorouracil. And it's given over 24 hours. So it's an extra drug compared to the ECX or ECF regimen. And in this randomized study, we see that there was an improvement in many, many features. So on the left we see an improvement in the pathologic complete response rate. Now for esophageal adenocarcinoma, you see different histologies. We didn't talk about that that much but there's an intestinal histology, there's a diffuse type and then there's mixed. And in this study, they were able to look at the differences there. It really looks like the intestinal type, which is the Barrett's esophagus, the intestinalization, that's the type that really benefited the most from the FLOT. And I think that's the type that probably benefits the least from chemoradiation. On the bottom left, you see the adverse events. Neutropenia, 20% had infection. So in this study, they didn't use prophylactic growth factor support, but that's what we do in our practice because of this high rate of fever and neutropenia. But then you also see the diarrhea, nausea, fatigue and things like that. On the right is the survival curve. And you can see the use of FLOT is significantly better than the previous regimen, which was epirubicin, cisplatin and 5-FU, 50 months versus 35 months. The hazard ratio of 0.77. And at 5 years, you're still getting a 10% improvement in 5-year survival rate, 45% versus 36%. So that's actually become the standard particularly for adenocarcinoma that's locally advanced esophageal cancer.

So how do we improve on FLOT? And this is just a press release. So we don't have any of the details here. But it basically highlights that this study was a positive study in terms of the primary endpoint, which is event-free survival meaning adding durvalumab, which is a PD-L1 inhibitor, to FLOT improves event-free survival.

And so the MATTERHORN study is shown here. It's perioperative FLOT, which is the current standard, and they randomized patients to receive either durvalumab or placebo. This was a large study, almost 1,000 patients were randomized. It was a 1:1 randomization. And we have already some data that adding durvalumab does improve the path response rate. It's hidden behind that yellow bar, but basically it's about 18% versus about 7%. So you have a higher complete response rate and we now know that there's also a positive event-free survival endpoint. And I think — you'll have to invite me back to review the results once they are around. I think it's going to be presented at ASCO.

So just like patients who receive CROSS and then have residual disease then get immunotherapy for a year, now patients who receive FLOT likely they'll be able to get durvalumab before and after the surgery and probably for a year as well. So I think immunotherapy, as Dr Love said, is actually in many contexts and many diseases.

So in summary, FLOT is the standard perioperative treatment for esophago-gastric cancer particularly adenocarcinoma. We didn't talk about this but the ESOPEC study compared FLOT to CROSS and in the adenocarcinoma population it does suggest that FLOT might be better and I explained why during the course of the talk.

CheckMate 577 is patients who receive the CROSS regimen, have surgery. If they have residual disease, they should get immunotherapy. We touched a little bit on mismatch repair disease, and I think Dr Kim is going to talk more about that in her session. But these patients are very, very sensitive to immunotherapy. If you have a newly diagnosed cancer that's localized/ locally advanced, before starting therapy, you need to check this. Because if they're mismatch repair deficient, then chemotherapy or cytotoxic therapy could actually not only attack the tumor but also attack the immune cells that are vitally important. So the current recommendation is either immunotherapy or going straight to surgery. And then we just talked about the MATTERHORN study. And then we didn't talk about this but after surgery there is a risk of having a positive margin. And you might consider radiation in that context. And so I think that's my last slide.

DR LOVE: So we've talked again all week about what happens in oncology when a study is positive. The first thing you see is a press release that states that there's a trial — we don't know any data specifics until we see the exact magnitude of benefit. It might be a positive trial but not positive enough to want to do it. I just found out for the first time from Manish that it's going to be presented at the ASCO meeting in June. So I guess we're going to get to see whether the FLOT regimen is going to kind of follow the trend of what happened with the CROSS regimen adding immunotherapy. And so we asked Michal to talk a little bit about some of the nursing considerations in this situation. But first, Brooke, just kind of curious. We're seeing the use of immunotherapy and checkpoint inhibitors in the localized adjuvant, neoadjuvant setting in a number of tumors, melanoma first, lung cancer is used a lot, breast cancer, triple negative breast cancer. Here you have a year of immunotherapy. How do those patients do during that year? What do you usually see?

MS PARKER: Typically with immunotherapy, and I'll kind of mention this later, they tend to be tolerated better than your traditional chemotherapy. So the main symptoms that we tend to see are fatigue, but they tend to be able to live a relatively normal lifestyle after going through kind of this major chemo and surgery getting back to kind of feeling good and working.

DR LOVE: Yeah, you can imagine they'd be fatigued just from going through all the chemo and radiation. Alright, Michal, let's talk a little bit about how you view these patients and some of the issues that come up.

MS SEGAL: So when we see patients that get either neoadjuvant, adjuvant, immunotherapy, like Brooke said, usually they'll tolerate things very well, get maybe some fatigue, maybe some other usually not many side effects. We do warn them though to just let us know of any big changes. Because rarely patients can have one of the itises, which can turn into a big inflammatory response, which I'm sure Brooke will talk about a lot more later. We do want to give them the whole spectrum of possible side effects so that they know to report things to us.

So I'm going to talk about the management of locally advanced GEJ cancers, gastroesophageal cancers.

So known risk factors for esophageal and GEJ. Known risk factors can be divided by location and histology type.

Risks for esophageal squamous cell cancer include tobacco, alcohol, HPV infections. For esophageal and GEJ adenocarcinoma, risk factors include tobacco, obesity, GERD or Barrett's esophagus. Additional risk factors include our age, with mostly these happening in people over 50, and sex, with most patients being male.

Known risk factors for gastric adenocarcinomas include a diet with fried foods, salted meats, nitrates, pickled vegetables, infections with H. pylori, which can cause atrophic gastritis, tobacco, having a high BMI and environment exposures. Gastric cancer is also associated with several rare genetic risk factors.

So just reviewing. We talked about this previously. But some common presenting symptoms that people come in with often time with unintended weight loss, difficulty swallowing, painful swallowing or sometimes just the cough, hoarseness, symptoms of GERD.

So typical side effects with chemoimmunotherapy and/or radiation. Chemotherapy can cause fatigue, nausea, vomiting, loss of appetite, weight loss, diarrhea, mucositis, hand-foot syndrome, photosensitivity, alopecia. And sometimes patients suffer from actually side effects from the supportive medications we give, especially the antiemetics can cause constipation. Immunotherapies usually have little to no side effects but they can cause autoimmune-like inflammations to any part of the body such as like a colitis or nephritis or even myocarditis. RT radiation can overlap with many chemotherapy effects like fatigue, nausea, skin changes and changes or worsening to swallowing.

Prevention and management. Most chemotherapy regimens have built-in antiemetics on day 1 and then we also send prescriptions off for patients to take at home. We stress for our patients to be proactive and aggressive with any PRNs they have including over-the-counter measures. We stress weight maintenance with caloric intake goals and preferably high-protein foods. Patients are instructed to stick with small, frequent meals, calorie dense foods. And we encourage patients to liberalize their diets and be creative with different textures like soft foods or puree. Patients should be encouraged to call their doctor's office and report symptoms and not try to be a hero or be brave. We're here to help them and coming in for hydration, for example, can really help them get through planned therapy. For fatigue, the best approach is to take things easy. Other symptoms can be prevented like with a mouth rinse for mouth sores or using SPF30 sunscreen at least or wearing a hat and long sleeves. Good hand hygiene can help prevent infections as can avoiding sick people if possible.

Post-op management. After surgery, they might have a significant course of recovery before they can start adjuvant therapy. Immediately post-op they usually have a feeding tube, so that can remain in place for a few weeks after discharge. Weight loss is anticipated and it's helpful to reassure patients that this is an expected side effect and then they have to take things slow and be patient. Again, eating slowly, chewing food very well, having frequent small meals is the best approach to eating after surgery. Hydration is important but drinking should be limited during meals. Encourage your patients to use supplemental drinks or meal replacement things. Avoid spicy or fatty foods. And sometimes for people it's better to avoid carbonated drinks. It's helpful to frame for your patients to think food as a medicine that they have to follow a schedule and really make it a priority for their daily intake. A food tracking app can be helpful.

Supportive care. So outside of the primary care team, there's a whole host of supportive care services and options. Nutrition or a dietician can be very helpful with guiding patients on how and what to eat. They give great ideas for how to make foods more calorie dense. Social work is helpful with logistics for travel and home care if needed. Integrative medicine is a great referral. They can offer alternative treatments for better overall health.

Okay. So this is my little case study. A 60-year-old male with history of GERD, presents with 2 months of progressive dysphagia accompanied by a 10-pound weight loss. Endoscopy was done last week and it revealed a partially obstructing mass at the GE junction extending into the cardia. Pathology confirmed poorly differentiated adenocarcinoma.

So what are the next steps? So from the clinical team obviously we're going to want to complete the stagings. So Dr Shah mentioned a little bit. We're going to do imaging, like a PET or a CT, and we'll do an EUS or laparoscopy. From the nursing perspective, we know how overwhelming this life-changing scenario is and the first thing we can do is just be present and to support patients through their initial questions and needs. This is also obviously the same approach we use when first meeting patients who are newly diagnosed with metastatic disease as well. Getting a good baseline assessment is helpful for weight loss. Any eating or drinking issues or any pain. If surgery is indicated, eventually educate on the plan, the schedule and the next steps. Immediately we schedule for typically we schedule for Mediport and we get some basic labs, EKG. And then also we assess our patients for any support needs they might need. We also include a discussion about biomarkers and genetic testing and why we do them. And we review the implications of those results. My suggestion is that I try to break up my educational sessions into the first few clinical appointments or with follow-up phone calls so that patients aren't overwhelmed with a ton of information all at once.

Incorporation of Immunotherapeutic Strategies for HER2-Negative Metastatic Gastroesophageal Tumors

DR LOVE: Alright, let's talk a little bit — we'll kind of move on now and talk about metastatic disease. Unfortunately a very common scenario. We're going to talk about HER2-negative metastatic disease. Also we'll talk later on about patients who are HER2-positive. But Sunnie, we asked you how you think through initial treatment for metastatic disease, particularly the most common approach, which is chemotherapy and immunotherapy together.

DR KIM: Thanks for inviting me. I'm happy to talk about this topic. So I'll be discussing how we incorporate immunotherapies for patients with HER2-negative metastatic gastroesophageal tumors.

So I'll start with our patient case. This is a 67-year-old woman who presents with abdominal pain, new anemia and weight loss. She undergoes an endoscopy, which shows a fungating mass in the gastric body. The biopsy shows moderately differentiated adenocarcinoma with signet ring features. She has a CT done of the chest, abdomen and pelvis, which shows liver lesions, lung nodules and peritoneal thickening, unfortunately consistent with metastatic disease.

So what are our next steps? There are a growing list of biomarkers that need to be tested with gastroesophageal cancers. Some in the localized setting but definitely in the metastatic setting. And these biomarkers include PD-L1, namely the combined positive score, mismatch repair deficiency or MSI-high, microsatellite testing, HER2 testing, now claudin 18.2 testing. And then there are these rare genetic alterations, NTRK fusions, EBV amplification, EGFR amplification, BRAF V600E mutations and RET fusions. And the 2 I want to highlight here are PD-L1 and MMR/MSI because these biomarkers do guide us to incorporate immunotherapy drugs.

So what is a PD-L1 combined positive score? The way this is calculated is the pathologist takes a look at the tumor underneath the microscope and stains it for PD-L1. And CPS is calculated by the PD-L1 staining on tumor cells and immune cells like lymphocytes and macrophages over the total viable number of tumors x100. And that is our CPS.

So going back to our patient case, our 67-year-old woman with Stage IV gastric cancer. We do biomarker testing. We find that she's proficient in the MMR proteins. Her PD-L1 CPS score is high at 10. HER2-negative and claudin 18.2 negative. So we start her on chemotherapy FOLFOX plus nivolumab.

So what is the data behind using these immunotherapy drugs with chemo? There were 3 Phase III trials that combined a PD-1 inhibitor with doublet chemo versus chemo alone in patients with advanced unresectable gastric/GEJ cancer adenocarcinoma. So I listed the trials over here. And you can see that there was an overall survival benefit when you added the PD-1 inhibitor.

But I think really importantly is, how does a PD-L1 score affect clinical outcome? So I took one of the studies, the CheckMate 649 study where they combined nivolumab to doublet chemotherapy. And what we see is in allcomers there was a survival benefit, 13.7 months versus 11.6 months. But as the PD-L1 CPS goes higher, so greater than or equal to 1 and greater than or equal to 5, we see the difference between the 2 groups increase. So in the PD-L1 CPS greater than or equal to 5, the median overall survival is 14.4 months versus 11.1 months. And I think very importantly, that 60-month overall survival rate. So patients who are experiencing a longer survival period. That can go up to as high as 16% if you have a high PD-L1 score.

This was another study, KEYNOTE-859 where they combined a different PD-1 inhibitor, pembrolizumab, to doublet chemotherapy. And same story. When the PD-L1 CPS is greater than or equal to 10, on the right side, you see the survival difference also become more dramatic.

So this patient who started on FOLFOX/nivo, at the next restaging scans, the liver lesions fortunately have decreased in size and there is decreased gastric wall thickening. And this woman did experience disease control for 2 years on this treatment before disease progression.

And quickly going into patients who have mismatch repair deficient or MSI-high gastric and GEJ cancers, as I alluded to before, there are 4 mismatch repair proteins that need to be tested, MLH1, PMS2, MSH2, MSH6. And these proteins are very important at repairing DNA base pair mismatches. And so when we talk about, are the proteins present or not, the tumors again are looked underneath the microscope and they're stained with these protein antibodies. When it's dark brown on the bottom, that means that the protein is present. On the top 2 boxes, where you don't see that brown stain, that means those proteins are not present. And the implications of this is that when these mismatch repair proteins are altered, you develop these microsatellite repeats in the DNA and this produces that high mutational burden that we discussed and it makes it exquisitely sensitive to immunotherapy drugs like PD-1 inhibitors.

So these were 2 studies that were done to evaluate the benefit of chemo plus a PD-1 inhibitor in gastric and GEJ cancers. And what we found was that the patients who had MSI-high tumors, and it's a small number, on the bottom you can see the numbers, we're talking like 15 patients in each group. When the patients received immunotherapy alone or immunotherapy plus chemotherapy, their survival was much better than patients who received chemotherapy alone. So that is a recommendation we have for MSI-high tumors.

Just another study showing the same effect. CheckMate 659, which is first-line chemo plus immunotherapy, nivolumab. We found for the patients who were MSI-high the addition of nivolumab significantly improved the survival compared to chemo alone. You don't see as much of that benefit in the microsatellite stable tumors on the right.

So what are my recommendations for when to use a PD-1 inhibitor? For patients who have mismatch repair proficient gastric GEJ cancer, it's very reasonable to add a PD-1 inhibitor to doublet chemo for PD-L1 CPS positive tumors. And we know that the higher the PD-L1 and CPS, the greater the benefit. For patients who have MSI-high tumors mismatch repair deficient gastric cancer, definitely want to incorporate a PD-1 inhibitor either by itself or with chemo.

DR LOVE: So I want to ask, Manish, you know, one of the challenges here and we've been again talking about this all week. In oncology, often we have multiple agents with the same mechanism of action and trials looking at that in various situations and then you have to choose. We've been talking about PARP inhibitors. There are a number of them approved. You rarely see trials that compare one to the other and so you have to indirectly compare it, which is not a perfect situation. Here's a good example here. The very common use of a checkpoint inhibitor in advanced gastric cancer in combination with chemotherapy as first-line. And you see you have pembrolizumab, tislelizumab and nivolumab all with pretty similar results. And we don't have any trials kind of comparing them. Can you talk a little bit, Manish, about how for practice when you're in this situation and other situations with immune therapy in a gastroesophageal cancer, how you choose which checkpoint inhibitor you're going to use?

DR SHAH: Yeah, that's a really important question as you highlight. So the first thing I'll say is that not — so these 3 are all PD-1 inhibitors. The interaction at the T cell level is PD-1 on the T cell with PD-L1, which is on either the antigen-presenting cell, like a lymphocyte or dendritic cell, or the tumor. So there are other drugs like durvalumab or avelumab, which are PD-L1 inhibitors. And then there are these 3 approved PD-1 inhibitors. And despite the 1000s of patients that have been on immunotherapy checkpoint inhibitor trials, to my knowledge there have been none that have been comparative between these PD-1 inhibitors. So I think it makes it challenging.

The other thing that is important is the scoring system. As Dr Kim mentioned, the higher the PD-L1 staining, the more the benefit of the checkpoint inhibitor. So each of these 3 trials actually use a different system for evaluating PD-L1. The RATIONALE trial, in particular tislelizumab, used something called the tumor area positivity, TAP. And there is good concordance between TAP and CPS but it's not 100%. It's not 1:1. It's like 90% concordance. The FDA looked at this in September last year and, in fact, for the RATIONALE package insert they just said that you have to be PD-L1 positive. And they didn't actually specify what testing mechanism there is. So those are some of the nuances with regard to the testing of the biomarker and the differences in the checkpoint inhibitor.

I think practically people sometimes choose based on how convenient it is. So nivolumab is given every 2 weeks. It is a good partner with FOLFOX, which is given every 2 weeks as well. Pembro typically is given every 3 weeks so you have a mismatch between FOLFOX and pembro. But if you're using platinum and capecitabine, maybe pembro makes more sense. Tislelizumab is also an every-3-week regimen. But then the companies are very smart. They gave us another formulation of pembrolizumab, which is now every 6 weeks. So if you wanted to you could give pembro every 6 weeks with every third cycle of FOLFOX. So that reason kind of goes out the window as well. So I think, you know, if you ask me how I choose, I think — so the other part I should mention is that in Dr Kim's case study the patient was on treatment for 2 years. Most of that time is not on chemo, it's mostly on immunotherapy. And so giving immunotherapy less often like pembro, an IV, or now they have a subQ formulation every 6 weeks, is kind of compelling. So tislelizumab is pretty new. I think it's a very good drug, but I haven't used it yet because it just got approved. And I would say in my practice probably about 60% of the time I use nivolumab and 40% of the time I use pembrolizumab. Part of it depends on the regimen that I'm using. Part of it depends on if I think that they're going to end up going every 6 weeks because of travel issues. It's really a personalized option. And I think, you know, and I want you to also understand this is not a negative thing. It's good to have options because you can now tailor the therapy to your patient in subtle ways because I think they're all probably very, very similar.

DR LOVE: Sunnie, anything you want to add to that? We were talking this morning about the fact that oncologists tend to follow the data and when they see a trial, even though there are multiple agents in the same class, when they see a new trial in a different situation and one of those is used, they usually use that one. Other than that, often they use the first one because they kind of get used to it. But the analogy that I made today and related to checkpoint inhibitors in lung cancer where pembrolizumab was used all the time with metastatic disease and then a trial came out in locally advanced disease and the data that looked best was durvalumab so everybody started using it. Even though they thought it was probably the same thing, they used durvalumab. So we'll see as checkpoint inhibitors become used in other situations. It really depends on which one is used. Anything you want to add, Sunnie, in terms of how you choose IO?

DR KIM: I would agree. It's nice to have options. Now that we've had some more longer term data with CheckMate 649, which is the nivo, and KEYNOTE-859 with the pembro, we actually find when we compare at least the hazard ratios, which is a measure of how much the experimental arm is better than the control arm, those numbers track really nicely between the trials. And so I think that's given us more confidence that the drugs are very similar. The magnitude of benefit is also very similar too.

DR LOVE: Another example we talked about Wednesday night is in breast cancer with CDK inhibitors. Again, 3 agents that seem very similar and then as the patients were followed, one of them, ribociclib, all of a sudden started to show a better survival advantage so everybody switched over to that. So we'll see how this evolves over time.

DR KIM: I think it's important to note that this is an evolving field and we are continually reevaluating the data with every new data release.

DR LOVE: Alright, Brooke, let's continue our discussion actually from this morning. And we could talk again all day long about managing patients on immunotherapy checkpoint inhibitors.

MS PARKER: Well, thank you. Yes, I'm talking about nursing considerations for patients receiving anti-PD-1 and PD-L1 antibodies.

So setting the stage in how this works. Well, we all know T cells, which are part of our immune system. And these T cells in this case help detect and destroy cancer cells. Well, these T cells have PD-1 proteins on them, PD-1 receptors, that when activated downregulate our immune response. On the other hand, tumors have PD-L1 proteins on them and when these proteins bind with our T cells' PD-1 receptors, it effectively turns off our T cells, prevents them from finding these cancer cells and destroying them. This is called the PD-1 pathway.

So how does immunotherapy work? Immunotherapy works because these anti-PD-1 and PD-L1 antibodies will bind with their respective receptors, the PD-1 and the PD-L1, to prevent this pathway from occurring. And this keeps our immune system working and fighting these cancer cells. So, as Sunnie mentioned, we give this to gastroesophageal patients who have either high PD-L1 expressions or are MSI-high or mismatch repair deficient.

So how do these affect patients? Typically these are much better tolerated than your traditional chemotherapies, but it's still important to know what to be on the lookout for. So the typical onset is about 3 to 6 months, but we can see toxicities happen after 1 cycle and even after treatment has been completed. So as you can see the most common side effects are fatigue, skin changes, pneumonitis, hormone related changes like hypothyroidism. Most of these toxicities stem from treatment causing your immune system to go too active, to start attacking healthy cells, kind of like an autoimmune disease. So this is important because although rare it can impact any part of your body as you can see in this picture. So as a nurse, if you're listening to a patient's symptoms, it's important to cast a wide net of differentials because with immunotherapies we can really see it impact a lot of different areas. And then one thing I wanted to add. So most of these side effects tend to not be severe or life threatening and these are all based off of single agent immunotherapies. But if you're looking at a combination immunotherapy, these occurrences do go up.

And in this right upper hand graph, you can see kind of the expected timing of some of these toxicities and their duration as well as severity. So for something like skin toxicities, they might start earlier on in treatment and be less severe. Whereas something like pneumonitis we'll see farther along in treatment and is obviously more severe.

So your patient is about to start treatment. What do you tell them? Well, overcommunication. Because the earlier we can diagnose these toxicities, these adverse events, the quicker we can at managing them. So it's important to give patients kind of a list of symptoms of when they should contact clinic. I'm not going to go over all of them in this slide, but you can always refer back to it for ideas.

While on treatment we monitor for these toxicities at every visit. So that includes physical exams, blood work, vital, interval histories and then as well as periodic imaging. If we do find a toxicity on the immunotherapy, then the course of treatment depends on the severity of this toxicity. So we grade them, Grade 1 mild, Grade 5 death. So if these toxicities are anywhere between Grade 3 or Grade 4, then we're going to stop treatment and pursue high-dose steroids with a long taper. If this doesn't work, then we move on to immunomodulators. The one exception to this is hormone toxicities like, once again, hypothyroidism. For that we'll just do a hormone replacement for.

The one clinical experience that I did want to bring up is a patient with gastric cancer who began FOLFOX plus nivolumab. He was on this treatment for 2 months when he came to clinic and reported 8 episodes of diarrhea a day. This was a huge change from his baseline. Grade 3 diarrhea. We did a GI PCR that came back negative. So it led us to believe that the most likely cause was an immune-related colitis. We promptly started him on steroids. But what we did not take into consideration was that he was a type 2 diabetic. So next week he came back and as you can imagine his blood sugar was through the roof. And so we had to get his primary care provider involved to start him on insulin. And the reason why I bring this up is because as nurses even when patients are on these high-dose steroids, they require a ton of monitoring. Especially if they have something like diabetes, these steroids can potentially put them in a dangerous situation and you might need to get the help of a primary care provider or an endocrinologist on hand to further monitor.

DR LOVE: That's a great point there. We were talking the other day. There are a bunch of new drugs in breast cancer also, oral drugs, that cause hyperglycemia. Michal, any thoughts about this case that was just presented in terms of not only the colitis and how it presented but the issue with the steroids? And also anything you want to say about skin changes that you see with immune checkpoint inhibitors?

MS SEGAL: Yeah, for sure. That's a great example you have with the diarrhea. We had a patient similarly recently who also had like a great change in diarrhea. Went from like baseline normal stool to like 8 or 10 times a day. He ended up actually having, I think, norovirus. So we ruled out other reasons and he was hospitalized for that. And then a few weeks later, again he had another like his diarrhea never really resolved and then all of a sudden it upticked again to like 8, 10 episodes. So he was rehospitalized. They did a scope, which is the only way to really definitively diagnose colitis, and then he ended up having IO-related colitis. So he's been on a steroid taper again with PCP prophylaxis and a PPI. Like Brooke said, the taper is over 4 to 8 weeks so it requires very close management. We involved our gastroenterology team to help manage the taper. As for skin changes, some people, as Brooke said, it's probably the most immediate side effect if they will have IO side effects to the skin. Sometimes people have even days 1, 2 and 3 like an immediate itchiness and not necessarily a rash but just full-body itchiness. We monitor it. If it continues or if it turns into rashes or it's very persistent, we'll refer to dermatology.

Role of Therapy Targeting CLDN18.2 in Advanced Gastric/Gastroesophageal Junction Adenocarcinoma

DR LOVE: Great. So we're going to move on now and talk about again one of the most exciting advances in oncology, the use of the agent zolbetuximab and claudin 18.2. Manish is going to talk about what that is. And Manish, just to let you know, we do videos with general oncologists in practice all the time asking about our cases. I was doing a video with a doctor in North Carolina, really intelligent, on top of everything. And zolbetuximab had just come out. And I said, have you used it? Yeah. And the first thing of course I asked him was, how did the patient do? And he said, well not too well, a lot of nausea and vomiting, other patients were upset. Because he told me, he said he’d heard a program we did about it. And I said, did you hear about slowing the infusion down? He said, I didn't know about it. This was the first patient I ever treated. And so these drugs come out, they get used right away and it takes awhile for people to get used to it. But hopefully, the earlier the better. And that's why we're going to talk about it right now. So Manish?

DR SHAH: Great. Thank you. Let me first say just very quickly about the diarrhea in the last session with immunotherapy checkpoint inhibitors. I wanted to call out that ONS actually has a great fact card that I actually use in my practice all the time for patients because it tells you, you write down what regimen you're getting and that it's an immunotherapy modulator and things like that. Because patients, what I think from an education standpoint, the earlier you act on the diarrhea, the better it can be managed. And so thank you for that and that was a great session.

But from a physician education standpoint, as you pointed out, Dr Love, zolbetuximab is really a great drug. But it's like everything, we just need to make sure we know how to use it the right way. So let's go through some of the data here. So this is an 85-year-old gentleman. He's got heart failure, hypertension, hyperlipidemia. He's got bilateral nephrectomies from another condition. So he's got a directed donor kidney transplant from a few years ago. He presents with a 1-year history of fatigue, abdominal pain and weight loss. And ultimately, as we talked about before, he does have an adenocarcinoma that's at the lower part of the esophagus. It does have signet ring features. That's the bottom panel on the right. On the top 2 panels, you see lymph nodes in the neck. So this is metastatic disease. The patient, you know we talked about biomarkers, he's MMR proficient so we're not thinking about immunotherapy. But he's PD-L1. CPS is 20%. It's high. And the claudin 18.2 is 80%. That's also high. So for zolbetuximab, the threshold is 75% or higher. So he can get zolbetuximab. And for checkpoint inhibition, the threshold is positive. But the higher the number, the better your outcome is going to be. So 20 is very high. And I just talked about the PET scan already.

So in terms of our options, we can do chemotherapy plus immunotherapy, chemotherapy plus zolbetuximab with claudin 18.2 inhibitor or chemotherapy alone. And I think the teaching point here is that the patient really has a pretty strong contraindication to immunotherapy. He's got a directed donor kidney transplant. So there's like a 30 to 40% rate of graft rejection because of the immunotherapy. So that's something that you would really probably not want to do.

This is a nice schematic of the different markers that we've been talking about. Again, HER2, mismatch repair, PD-L1 and claudin. And then hopefully in the next year or so we're going to get data on bemarituzumab, which is an FGFR2 inhibitor. The one thing that I don't like about this slide though is that it kind of suggests that the biomarkers are mutually exclusive. So if you're PD-L1 positive, you might not be claudin positive. But that's not true. About 15% are overlapping between claudin and PD-L1 positive. About 30% might be overlapping between HER2 and claudin. So we're going to have a situation where you have dual biomarker positivity and you're going to need to make a decision on how to treat a patient because we don't have comparative data in that regard. So that's just something to keep in mind as we move forward.

Claudin is a normal protein in the gap junction. So on the left you have the normal gastric epithelium. You have the lumen at the top and you have the interstitial area on the bottom. And the reason why there's a gap junction is because you want to be able to separate what's happening in the stomach to what's happening inside the body. So these gap junctions are very tight. They don't let material pass. And so the material has to pass through the cell and it can get processed. But as the cancer develops, you lose cell polarity. And the way you do that is that you lose the connections in the gap junction. By doing that, the proteins in the gap junction, like claudin, become exposed and then become available. So because it's becoming available, zolbetuximab, which binds to claudin, it then activates an immune response. And what we have shown is that when you add zolbetuximab to chemotherapy, you can have an improved survival.

So there are 2 large studies that looked at this, SPOTLIGHT and GLOW. And this is a combined analysis that shows that the addition of zolbetuximab to chemotherapy improved both the progression-free survival, that's on the left, and the overall survival on the right. And the hazard ratio is about 0.7 to 0.75. So it's a significant improvement. The other thing I'll point out from these curves is the tail on the curve. So looking out at 36 to 40 months, 3 to 3.5 years, you're seeing really a doubling of survival, both progression-free and overall survival. That's very similar to immunotherapy, which is in line with how we think zolbetuximab works. It activates the immune system to the cancer by binding to the claudin protein that's exposed. And then on the bottom is the thing that happened with the physician that Dr Love mentioned. There is a high rate of nausea and vomiting about 2- or 3-fold higher with zolbetuximab than without zolbetuximab. Now remember claudin is a normal protein. It exists even in the normal gastric mucosa. So we think that the nausea and vomiting that people have is almost like an on-target effect. When you're in the middle of nausea and vomiting, patients don't find that data reassuring. But I think it is an on-target effect. But the main point though is that if you're able to get the patient through the first 1 or 2 cycles of therapy, they tolerate it much, much better. So you just need to support them through the first 1 or 2 cycles. And we actually wrote guidelines on how to do that. You have to hold the infusion, give some steroids, give more antiemetics, slow it down and you'll get them through it. And the other thing that's really important is counseling. You tell them to expect it. This is expected and then people get through it.

So across essentially all the different categories, zolbetuximab did seem to have benefit. There's one category, the GE junction tumors here, that seemed perhaps it was closer to neutral. We still need to understand if this is a real finding or this is an artifact because if you're looking at a lot of variables this, you know, it could happen by random that one of the variables was not positive. And this is that guideline that I was mentioning before. And just, you start at the very top, you do use prophylaxis before the infusion. That includes your NK-1, aprepitant and ondansetron and steroids. In our clinical trials, we didn't use steroids because we didn't want to block the immune response, but I think we want to overcome the nausea that people have. So you use very strong antiemetics from the beginning. And then if you experience nausea alone or vomiting, you can add antiemetics, that's what they say, but then also you can adjust the dose, I mean, the rate, you can slow it down or you can even hold the therapy for like an hour and then resume treatment. So that's the other aspect of it. The first dose is given over 3.5 to 4 hours on the very first day and then you give FOLFOX. So if you're going to give the treatment, you have to start early, 8:00 AM or 8:30 because the patient is going to be there the whole day. So that's another kind of key thing. You don't want to rush through it.

And then the last thing I want to mention is that zolbetuximab is just the first drug in this class of drugs that are targeting claudin. And that just highlights the pace of drug development, drug discovery that's going on. I mean, if you think about it, trastuzumab, which is targeting HER2, was developed 30 years ago. And we're just now getting trastuzumab, deruxtecan, tucatinib and other, zanidatamab, other drugs that are targeting HER2. Zolbetuximab was approved last year and we have 16 drugs that are in the pipeline being tested. And they're all a bunch of different types. There are CAR-T therapies, bispecific antibodies and antibody-drug conjugates, which are on the far right. So it's an important thing for drug development because it means that the horizon of your drug on the market may not be as long as it used to be. That'll be important moving forward.

So back to our case. He did receive zolbetuximab with FOLFOX. He had a response to therapy and he's doing well and his kidney function is still going strong. So kudos to him. I think that's my — oh, so just to conclude. Again the biomarkers are important. So a newly diagnosed patient I just can't emphasize this enough. From the beginning, get the biomarkers, PD-L1, HER2, mismatch repair, claudin and then I think in the next year or so we'll need to get FGFR2 as well. For PD-L1 positive tumors, in general, you would use immunotherapy. If you're claudin positive, you would use zolbetuximab. If you're dual positive, we don't have data to tell you which one to use. And so this will — I'm sure Dr Love is going to make me answer that question at some point. And then if you're HER2-positive and PD-L1 positive, you use immunotherapy, trastuzumab and chemotherapy as Dr Kim pointed out.

DR LOVE: So yeah, so important to keep in mind. This is a different mechanism, nausea and vomiting, which is normally central. Now you're talking about what we think is a direct effect. And also the idea of getting that patient though and focusing on that first infusion. Tonight we're going to talk about obinutuzumab, the anti-CD20 antibody. Very bad infusion reactions, not nausea and vomiting, infusion reactions but once you get them through it, they do well. So a lot of attention to the initial management of this situation. Also just to note, we had an extensive discussion, so we're not going to repeat it today in the endometrial session today, about potential contraindications to IOs. This case here with a kidney transplant, important consideration. You have a patient with hepatic or cardiac transplant, that gets a lot more difficult. But also prior autoimmune disease. So Sunnie, curious about what your experience is with zolbetuximab particularly in terms of side effects and answer the question that Manish brings up. If this patient didn't have the prior transplant, would you consider or could you give an IO and zolbetuximab?

DR KIM: So we did treat our first patient with chemo plus zolbetuximab in late 2024. I think one thing to note is that this patient had already had his primary tumor resected and we seem to think that patients who still have their tumor intact in the stomach or the GEJ may actually experience more nausea, vomiting that, you know, on-target effect that Manish was talking about. So he had no nausea/vomiting. And I'm a little bit ashamed to say this but we actually ran the infusion way too fast by accident and even with that he had no nausea/vomiting. But I recently saw a patient who saw me for a second opinion and she told me that her zolbetuximab had run over 2 hours, which is way too fast, and she said it was worse than the FLOT she had received. And so I think this just highlights again how important it is to work with our clinical pharmacists to make sure we start at a slower infusion rate. Because the first dose is higher too, it's kind of like a loading dose almost. And if they have nausea/vomiting stop, slow it down, give them supportive medications. And, at this point, we have a quadruplet antiemetic regimen including olanzapine to start with and those patients I think are doing okay.

DR LOVE: So Michal, we always turn to the academic centers when a new drug comes out because you all see it. You see it during the trial setting. I'm very curious to hear what you have to say about management of patients getting zolbetuximab.

MS SEGAL: Thank you. So just some background. About 50% of patients do present with metastatic disease at the time of diagnosis and nearly all will develop disease progression. Even patients who present with resectable disease have a high rate of recurrence. And the 5-year survival rate for advanced disease is roughly 7%. So this is an aggressive disease and treatment for advanced disease is palliative in nature. The chemotherapy backbone is a 2-drug combo with a fluoropyrimidine and a platinum, so typically FOLFOX or CAPOX. Based on biomarkers, we can now offer add-on targeted treatments with monoclonal antibodies such as nivolumab or pembrolizumab. And recently zolbetuximab has been added to our toolkit for claudin 18.2 positive disease. Biomarkers are essential for treatment planning. So in this diagram here you can see this is how I explain it to patients. We get a tissue sample from a biopsy usually with an endoscopy for this disease. We put the tissue on slides for pathologists to review. They perform staining and that's how we get biomarkers to help guide treatment. So I'm going to use this, Dr Shah said before, the issue is tissue. So that's how we explain to a lot of patients why we get so many endoscopies.

The carcinogenesis of claudin 18.2. So what is claudin 18.2? It's a tight junction molecule predominantly found in healthy gastric tissue and it becomes accessible on the tumor cell surface during malignant transformation thereby providing an appealing target for cancer therapy. It's not expressed on any healthy tissue except for the stomach limiting the accessibly to the antibody. Claudin 18.2 is also expressed in metastatic lesions.

The mechanism of action. I won't go too deeply into this. This is right from the zolbetuximab website. It's a first-in-class monoclonal antibody highly specific for claudin 18.2. Zolbetuximab depletes claudin 18.2 in two fronts, which you can see here this ADCC pathway and the CDC pathway. When combined with chemotherapy, it improves overall survival compared with chemotherapy alone in patients with claudin 18.2 positive and HER2-negative gastric or GEJ cancer. In the combined analysis that Dr Shah mentioned, SPOTLIGHT and GLOW, they screened over 4,000 patients and about 40% of patients were deemed to have claudin 18.2 positive tumors.

So on to side effects and patient education. Like mentioned before, the most common side effects with zolbi are nausea and vomiting. The GI adverse reactions occur most often within the first 30 to 45 minutes of initiation and the infusion. There's also a chance of a hypersensitivity or infusion-related reaction. These types of reactions would be managed per your institutional standards for specific symptoms such as diphenhydramine or fluids, et cetera. One easy intervention for the infusion nurses to do is to just reduce the initial infusion rate, which has been associated with lower severity of the GI toxicity and hypersensitivity. Outside of the infusion, there is a potential for overlapping toxicities with chemotherapy such as the nausea and vomiting but also abdominal pain, loss of appetite, weight loss. Hematological events can also occur like anemia and neutropenia. As we mentioned earlier, the stomach is the only tissue where claudin 18.2 is present on normal tissue in addition to malignant cells. So we do see the patients with prior gastrectomy, like Dr Kim said, often have less GI symptoms and tolerate therapy better.

Antiemetics in management. So where I work we follow ASCO guidelines. Drugs are typically broken down by their emetic potential here. Zolbi is considered on this spectrum very high to high. So we do follow this 4-drug regimen, this very aggressive antiemetic regimen. For day 1, they get 4 drugs of 5-HT3 receptor agonist so that's typically palonosetron. NK1 receptor agonist, aprepitant. And then we'll give IV dex or another steroid and also olanzapine orally. This states 5 or 10 but I think there is data that shows that even 2.5 mg olanzapine is also effective. Then for days 2 through 4, we give what's called like a delayed emesis regimen. So what we'll do is we'll send patients home with prescriptions for dex. For us, we do 8 mg PO once a day. We recommend to take it in the morning. And then we'll send them home with olanzapine 2.5 to take on days 2 through 4 at night because it can make you sleepy. But they can continue the olanzapine continuously if it is helpful.

Monitoring and support. We do stress to our patients the importance of taking the delayed emesis. So take the dex, take the olanzapine, take and maximize any PRNs they have like ondansetron. If they're not managing at home, not eating or drinking, make sure they know to call your office so we can arrange a check-in visit or even just schedule hydration. For your stoic patients who don't like to complain, a proactive check-in call can be very helpful. I'm sorry. I'm a little lost in my notes here.

DR LOVE: Let me just talk a little bit about what you talk to patients about in terms of diet.

MS SEGAL: Yeah, for sure. So again this kind of echoes the operative patients but liberalize your diet. Try to think out of the box. So eat breakfast for dinner. Try new foods that you may not think you like. Patients that have taste changes often with chemotherapy, they might eat things that they've liked their whole lives and then it doesn't taste the same or it tastes gross. So you just have to try new things and try different textures. So pureed, soft foods. Again same thing as operative patients, small, frequent meals, eating slowly, chewing your food very well, avoiding foods that are very rich or fried, greasy, spicy. Trying to eat calorie-dense, high-protein foods is the goal so you can try as best to maintain your weight.

DR LOVE: Anything you want to say about self-care measures?

MS SEGAL: Sure. And this goes in general with zolbi in combination with chemo, but really good oral hygiene. A mouth rinse even from day 1 preventatively to prevent mouth sores. Infection control. Just managing, I mean, washing your hands a lot. Taking over-the-counter drugs for constipation, diarrhea, taking pain meds. Skin protection is important. Moisturizing your skin, especially your hands and feet, and wearing at least SPF30 sunscreen if you're going to be out in the sun. Rest as needed. Plan your events and activities for time points that you know you'll have the highest energy. And there's a lot of nondrug therapies or interventions that patients can do especially if they're the type of patient that doesn’t like to use extra medications. So relaxation methods, music, deep breathing exercises, yoga, meditation, and even like acupressure or other complementary services that they can get through integrative medicine. And also just lastly do reach out to your social worker for ins into supportive groups. And also advocacy groups could be helpful to help patients cope through this time.

DR LOVE: So many great practical points. I love it when we can get into the nitty-gritty of what you do in your own practice.

Considerations in the Care of Patients with HER2-Positive Gastroesophageal Cancers

DR LOVE: Let's finish out talking about HER2-positive gastroesophageal cancers, particularly as it relates to gastroesophageal. We've talked a lot about T-DXd but let's talk about it in this scenario. A patient with HER2-positive disease with recurrence. Sunnie.

DR KIM: Yeah. So we'll start with a patient case. This is a 59-year-old man who presents with worsening dysphagia, weight loss and heartburn. An endoscopy shows a mass in the gastroesophageal junction and biopsy pathology shows poorly differentiated adenocarcinoma. Unfortunately, in this case, the CT chest abdomen pelvis does show multiple liver lesions concerning for metastases. Biomarker testing is done showing intact mismatch repair proteins, a PD-L1 CPS of 1, HER2 IHC 2+, and we'll go into that, and claudin 18.2 negative.

Our next steps? So going back to those listed biomarkers we keep emphasizing. In this patient's case, we're going to focus on that HER2 testing that was done. This was adapted from the American College of Pathologists showing what is our HER2 testing algorithm. Very similar to our patients with breast cancer. So once the tissue is obtained, we perform first an immunohistochemistry test, IHC. So if it's IHC 3+ strongly positive with that brown stain, no further testing is needed. This is considered a HER2-positive gastric cancer. If it's HER2 IHC 2+, this is considered equivocal where you need to then do this ISH testing, in-situ hybridization testing. And if that ratio is greater than or equal to 2, that's considered a positive HER2, a HER2-positive cancer. And then if it's IHC 1+ low staining or IHC 0, that's HER2-negative.

Just some pictures to show this. On the far right on the top is that very strongly brown staining gastric cancer, which we would consider 3+, and then all the way on the left would be HER2-negative where there's really no brown staining, 0. So from the second to right, that's that 2+ IHC staining gastric cancer. And this is where we reflect to in-situ hybridization. This is tagged with a fluorescent tag. And so if we see an amplification of the HER2 gene over the centromere in chromosome 17 greater than or equal to 2, that's considered I-S-H positive, ISH positive. And that would be a patient eligible for trastuzumab based therapy in the first-line setting.

So what is the HER2 overexpression patterns in gastroesophageal cancer based on location and histology? So by location, 30% of our gastroesophageal junction cancers are HER2-positive. This is higher than say our gastric body tumors of which 15% are considered HER2-positive. And then by histology, as mentioned before, there are different types of histology we can see underneath the microscope. For the intestinal type gastric cancers, again the highest proportion of HER2-positivity and then the diffuse type, which has incidence of HER-2 positivity, which is about 5%.

So going back to our patient case. The FISH is positive, greater than or equal to 2. And so the patient is started on FOLFOX, trastuzumab and PD-1 inhibitor, pembrolizumab.

So the data on which this was based is a trial called the KEYNOTE-811 trial. These were patients with advanced unresectable gastric and GEJ adenocarcinoma. This was a global trial. Had not received prior therapy in the advanced setting. And they were HER2-positive, again by the criteria we just mentioned. If they're IHC 3+, they were included or IHC 2+ plus ISH positive. And so they were randomized to receive a doublet chemotherapy regimen, pembrolizumab and trastuzumab versus chemotherapy plus trastuzumab. And I didn't put this in my slides but the benefit of trastuzumab with chemotherapy over chemo alone was already previously shown in a trial called ToGA. So these patients were then followed and what we found is that there was a survival benefit in patients who had a PD-L1 combined positive score greater than or equal to 1 with the quadruplet therapy. And this is now current FDA approval.

So why do we use it in patients who have the PD-L1 CPS positive score? So what they saw was that if you looked at tumors that were PD-L1 CPS less than 1 on the right side, we actually don't really see a benefit in either progression-free survival or overall survival. The benefit was seen more with the CPS greater than or equal to 1. So that's why the FDA label is as it is.

So moving forward, previously we tried a lot of the HER2 drugs that have been successful in breast cancer and they have just not been successful in gastric and GEJ cancer. Some of the thought being that a lot of the tumors actually lose their HER2 positivity after they've received trastuzumab. So it's not like breast cancer where I know we're treating these ultra-low HER2-positive tumors now. But we have had success with this newer drug, trastuzumab deruxtecan. So this is in a class of drug called antibody-drug conjugates. And the composition of this drug is on the bottom of the screen where it's composed of 3 components. You have the antibody, that Y-shaped structure, that binds to the protein of choice. And then you have a linker that links to what we call a chemotherapy payload. And this chemotherapy particle is hopefully able to get into those tumors that express the HER2-positivity. But another effect of it is a bystander effect where if there are cancer cells next to the HER2-positive tumor that don't express HER2, it may be able to kill those neighboring cells as well, which makes it a pretty powerful drug.

And the first study to really show its benefit was the DESTINY-Gastric01 trial. This was mostly done in Asia. These were patients who had received prior trastuzumab based therapy and these were patients who had progressed on greater than or equal to 2 prior lines of treatment including trastuzumab. And they were randomized to receive this trastuzumab deruxtecan every 3 weeks or physician's choice chemotherapy.

And what we found was there was a survival benefit in patients who had received trastuzumab/deruxtecan or T-DXd compared to this physician's choice chemotherapy. On average, a median duration of 12.5 months versus 8.9 months.

DR LOVE: So I know your patient had a great response to T-DXd for 6 months, but we're going to kind of move on. You can check out the slides and also some of the other slides that Brooke has that I don't think we're going to have time for. But I did want to ask you, Brooke, about a couple of things including your case. First of all, can you provide a little bit of an overview of the types of adverse effects you see with T-DXd?

MS PARKER: Yes, absolutely. So as you can see in this graph, most of the side effects tend to be more chemo-related side effects, which you kind of are probably pretty familiar with. But I wanted to highlight 2 side effects that are more specific to trastuzumab/deruxtecan. And that's interstitial lung disease and left ventricular dysfunction that we both have seen with this drug that are pretty important to educate patients on. For interstitial lung disease, you definitely want to make sure that patients are calling with signs of shortness of breath, chest tightness, coughing and things like that. And then left ventricular dysfunction, any type of weight gain, swelling in their legs or irregular heart rates then they definitely should be calling clinic.

DR LOVE: Let's hear a little bit about this case of a 64-year-old man with metastatic esophageal cancer who ended up getting treated with T-DXd, I guess last October until recently. What happened with him?

MS PARKER: Yeah, so it's actually a really interesting and recent case. He stopped treatment in early January just due to progression of disease and switched to paclitaxel/ramucirumab. And about a month into this new treatment, he came to clinic reporting shortness of breath. So we actually worked him up for thinking a pulmonary embolism. And the CT scan revealed bilateral ground-glass opacities and septal thickening. Kind of like what you would see in this picture. And so it was more clear like a pneumonitis that could be from this interstitial lung disease from this trastuzumab/deruxtecan. So ultimately we ended up starting him on steroids. The thing that I wanted to highlight with this case is one, it can happen after treatment ends. Although rare, it is definitely a possibility. And two, this patient actually got a CT scan a week prior to this and there were no signs of interstitial lung disease the week before. So if you have a patient calling in with shortness of breath or any worrying symptoms and they've just had a clear scan, that doesn’t mean you can rule out interstitial lung disease and should be brought in for further workup.

DR LOVE: That's a great point. A really interesting case. Thanks so much to the faculty. Come on back today, 6:00 PM. We're going to talk about non-Hodgkin lymphoma. Thanks so much. Thanks, Manish.